The overall objective of this project is to use human monoclonal antibodies (HMabs) as tools to gain a better understanding of the roles that human antibody-responses to variant and conserved epitopes of HIV-1 gpl2O play either in protecting infected hosts from disease progression or in promoting disease expression. We will produce human monoclonal antibodies (HMab) to gpl2O using EBV transformation of peripheral blood B cells obtained from asymptomatic HIV-1 infected patients. Because of overlap with a project with different aims which supports the production of HMabs to V3 epitopes of gpl2O, in the present proposal we will produce HMab reacting with non-V3 epitopes of pgl2O. Particular efforts will be made to select for HMabs that react with determinants of homologous strains that actually immunized each B cell donor. We will map the binding sites of all HMabs produced and characterize their biological activities with respect to their ability to inhibit virus infectivity, to mediate antibody enhancement of infectivity, or to mediate antibody dependent cell-mediated cytotoxicity. We will then use panels of HMabs to investigate the extent of antigenic diversity among HIV-1 isolates from different patients as well as sequential isolates from individual patients. HMabs will be ideal reagents for testing the hypothesis that immune selection of neutralization resistant variant viruses is associated with disease progression.